Flaviviridae
Dengue is a member of the Flaviviridae family which are enveloped, positive-sense RNA viruses whose human pathogens also include West Nile virus (WNV), yellow fever virus (YFV), Japanese encephalitis virus (JEV), and tick-borne encephalitis virus (TBEV) among others. Dengue transmission is through the bite of an infected Aedes aegypti mosquito that is found in tropical and sub-tropical regions around the world. Dengue fever (DF) is an acute febrile disease caused by one of four closely related virus serotypes (DEN-1, DEN-2, DEN-3, and DEN-4). Dengue fever is classified based on its clinical characteristics into classical dengue fever, or the more severe forms, dengue hemorrhagic fever syndrome (DHF), and dengue shock syndrome (DSS). Recovery from infection from one serotype produces life-long immunity to that particular serotype, but provides only short-lived and limited protection against any of the other serotypes.
Each year regional epidemics of dengue cause significant morbidity and mortality, social disruption and substantial economic burden on the societies affected both in terms of hospitalization and mosquito control. Dengue is considered by the World Health Organization (WHO) to be the most important arthropod-borne viral disease with an estimated 50 million cases of dengue infection, including 500,000 DHF cases and 24,000 deaths worldwide each year (36, 37). Dengue is also a CDC and NIAID Category A pathogen and in terms of bio-defense, represents a significant threat to United States troops overseas. Preparedness for both biodefense and for the public health challenges posed by dengue will require the development of new vaccines and antiviral therapeutics.
Orthomyxoviridae
The influenza virus is a member of the Orthomyxoviridae family. Each year regional epidemics of influenza cause significant morbidity and mortality, social disruption and substantial economic burden. During “flu season” it is estimated that influenza infects 10-20% of the US population resulting in over 100,000 hospitalizations and 20,000 to 40,000 deaths. The economic impact caused by influenza due to decreased productivity and increased health care utilization is estimated to be in the billions of dollars.
Recent emergence of highly pathogenic avian influenza (H5N1) has elevated our fears of a possible human pandemic. The current circulating H5N1 strain of virus is unusually pathogenic in birds causing destruction of domestic and wild bird populations. In rare instances, the virus has infected humans causing mortality in almost 50% of cases. Should this virus acquire genetic traits that increase person to person transmissibility widespread adverse public health and economic outcomes would be expected. FDA-approved antiviral drugs are currently in use, but increasing resistance to existing countermeasures necessitates the development of new antiviral therapeutics with novel mechanisms of action against influenza.
Poxviridae
Orthopoxviruses are members of the Poxviridae family. Human orthopoxviruses cause a spectrum of diseases ranging from severe disseminated lesional disease characteristic of the most common type of variola virus infection (variola major) to localized lesional infection caused by vaccinia virus. Of the several species of orthopoxvirus known to infect humans, variola virus, the etiological agent of smallpox, causes far more serious infections than the other species of poxviruses. While variola virus no longer exists in the environment, other orthopoxviruses continue to circulate and cause disease. Monkeypox virus, which is endemic in some areas of the Democratic Republic of the Congo, causes a zoonotic disease that is characterized by a generalized infection resembling a milder version of smallpox. Vaccinia-like viruses have been isolated from patients in Brazil presenting with localized lesions of the hands and arms and cowpox virus infections are increasing in certain parts of Europe. These viruses are believed to be maintained in the population through rodent reservoirs and zoonotic disease is thought to arise from contact with infected animals, or through an intermediate species such as cattle or domestic pets. Disease severity in all cases is influenced by the status of the host immune system, with individuals suffering from certain skin disorders or who are immunocompromised developing the most severe infections. Preparedness for both biodefense and for the public health challenges posed by human orthopoxviruses requires the development of new antiviral therapeutics.
Togaviridae
Alphaviruses are members of the Togaviridae family. Alphaviruses cause a spectrum of human disease ranging from asymptomatic infection to severe encephalitis and death. The virus is transmitted by mosquito and is maintained in the environment through an enzootic cycle involving infection of sylvatic hosts. Some alphaviruses achieve further amplification by exploiting domestic animals such as equines and pigs. Interest in alphaviruses has been renewed, because of reports that certain species of alphaviruses have been developed into efficient, stable biological weapons that are infectious by aerosol delivery and easily produced in large quantities. No licensed vaccine or therapeutic exists to treat or prevent infection of pathogenic alphaviruses. Moreover, the antigenic diversity of this group of viruses presents a formidable challenge for vaccine development. Thus, therapeutics that target conserved replication functions of the virus serve as useful countermeasures for treatment of alphavirus disease.
Bunyaviridae
Based on recommendations by the CDC and the NIAID, viruses that might be used as biological weapons have been separated into three categories. Category A viruses are considered the most serious threat to national security. These viruses have the greatest potential to cause widespread illness and death in human populations. Category B viruses are considered biothreats due to the potential for weaponization of these pathogens, and the projected high morbidity and mortality rates that would accompany their use as aerosolized agents. Category C viruses include emerging pathogens with the potential to be developed as biowarfare agents or to otherwise pose a risk to public health and safety. A national research and development effort has been undertaken to develop a comprehensive biodefense strategy against these agents. Of note is the presence of four different members of the family Bunyaviridae among the viruses characterized as biothreats to the United States. This fact reflects the diverse worldwide impact of bunyavirus infections on populations of livestock and humans. RVFV, a Category A bunyavirus, has been the cause of massive agricultural and social hardship in Egypt and the Arabian peninsula. Infections of as many as 200,000 people have been estimated in two epizootic epidemics resulting from RVFV transmission in 1977 and 1978, with an estimated 600 associated fatalities. The second of the Category A bunyaviruses, hantavirus, has been the recognized cause of significant morbidity and mortality among military and civilian populations for over fifty years. U.S. troops suffered from chronic exposure to endemic hantavirus during the Korean conflict, and, more recently, hantavirus transmission from rodent vectors to human populations has resulted in outbreaks of human disease and death in the American southwest. CCHF, a Category C pathogen, is a virus transmitted to humans who work in close contact with livestock in geographic regions that extend from sub-Saharan Africa to northern China. Infection with CCHF can lead to death in as many as 30% of diagnosed individuals. CCHF has all of the characteristics of the Category A viruses, except that current cell culture systems limit large-scale production capabilities; any technological advances in this area would elevate the risk posed by CCHF. The category B bunyavirus, La Crosse encephalitis virus, is the leading cause of pediatric encephalitis in endemic regions of the United States. To date, there are no specific vaccines or antivirals approved for the treatment of the Category A, B, or C bunyavirus infections in humans.
Arenaviridae
The arenaviruses are a diverse family of enveloped RNA viruses found worldwide. These viruses generate high morbidity and mortality and can be highly infectious by aerosol dissemination, promoting concern over their weaponization. Arenavirus infection in humans can lead to viral hemorrhagic fever, a serious illness characterized by extensive vascular damage and bleeding diathesis, fever, and multiple organ involvement. Arenavirus infection in rodents, the natural host animal, is usually chronic and asymptomatic. Five distinct arenaviruses cause severe HF in humans and are classified as category A pathogens, defined as those pathogens posing the greatest threat to public health and safety. These are Lassa fever, Machupo (causative agent of Bolivian HF), Junin (Argentine HF), Guanarito (Venezuelan HF), and Sabia, (Brazilian HF) viruses. Lassa fever is the most prominent biodefense target in this group, due to its current prevalence (estimated at up to a half-million cases annually, primarily in West Africa) and history of weaponization research. Junin and Machupo viruses (endemic in South America) were also reportedly pursued as biological weapons by the former Soviet Union. Preparedness for both biodefense and for the public health challenges posed by human arenaviruses requires the development of new antiviral therapeutics.
Filoviridae
Filoviruses including Ebola and Marburg viruses cause severe hemorrhagic disease in humans resulting in high mortality. Infections result from zoonotic transmission from an infected animal to humans. The natural reservoirs and routes of transmission are not fully understood. Person-to-person transmission occurs primarily through physical contact with infected material. No licensed vaccine or therapeutic exists to treat or prevent infection of filoviruses. Thus, therapeutics that target virus replication would serve as useful countermeasures for treatment of filovirus disease.
Retroviridae
The HIV virus is a member if the retrovirus family. Currently, over 42 million people are living with HIV/AIDS worldwide, and 74 percent of these infected people live in sub-Saharan Africa. By the year 2011, five countries (Ethiopia, Nigeria, China, India, and Russia) with 40 percent of the world's population will add 50 to 75 million infected people to the worldwide pool of HIV disease. An estimated one million people are currently living with HIV in the United States, with approximately 40,000 new infections occurring each year. FDA-approved antiviral drugs are currently in use, but increasing resistance to existing countermeasures necessitates the development of new antiviral therapeutics and treatment regimens/drug combinations to combat this lifelong infection.
Paramyxoviridae
Respiratory syncytial virus (RSV) is a nonsegmented, negative-strand RNA virus in the Paramyxoviridae family. The RNA codes for ten viral proteins—three are associated with the nucleocapsid (NS1, NS2, N), three with the envelope (SH, G, & F), two non-glycosylated matrix proteins (M and M2), a phosphoprotein (P), and a major polymerase subunit (L). RSV ollness begins most frequently with fever, runny nose, cough, and sometimes wheezing. During their first RSV infection, between 25% and 40% of infants and young children have signs or symptoms of bronchiolitis or pneumonia, and 0.5% to 2% require hospitalization. Most children recover from illness in 8 to 15 days. The majority of children hospitalized for RSV infection are under 6 months of age. RSV also causes repeated infections throughout life, usually associated with moderate-to-severe cold-like symptoms; however, severe lower respiratory tract disease may occur at any age, especially among the elderly or among those with compromised cardiac, pulmonary, or immune systems. RSV is spread from respiratory secretions through close contact with infected persons or contact with contaminated surfaces or objects. Infection can occur when infectious material contacts mucous membranes of the eyes, mouth, or nose, and possibly through the inhalation of droplets generated by a sneeze or cough. In temperate climates, RSV infections usually occur during annual community outbreaks, often lasting 4 to 6 months, during the late fall, winter, or early spring months. The timing and severity of outbreaks in a community vary from year to year. RSV spreads efficiently among children during the annual outbreaks, and most children will have serologic evidence of RSV infection by 2 years of age.
RSV infects most children by age 2 and is the leading cause of bronchiolitis and pneumonia in infants. It can also be a significant cause of disease in immunocompromised adults and the elderly. Estimates vary on the actual number of cases, the most important of which are those involving hospitalization. One report (CDC) estimates that up to 126,300 children are hospitalized in the US each year. Another report describes a more global view, which estimates that “a total of 18 million people annually become infected by RSV in the US, Japan, France, Germany, Italy, Spain, UK, including three million adults with underlying disease and almost 400,000 premature infants. Approximately 900,000 of the individuals in these risk groups are hospitalized for this infection each year.
Picornaviridae
Viruses in the family Picornaviridae replicate a positive sense, single-stranded genome and are transmitted as non-enveloped, infectious virions. Picornaviruses include the causative agents of such human diseases as the common cold, Polio, Hand-Foot-and-Mouth Disease, and Hepatitis A. These viruses are distributed across the globe, and a long-term international eradication effort is currently underway to control and eliminate poliovirus infection in humans. The significant respiratory and enteric disease burden caused by these pathogens worldwide has led to numerous campaigns to identify antiviral therapeutics and vaccines to combat picornavirus-associated diseases. Preparedness for the public health challenges posed by picornaviruses requires the development of new antibacterial therapeutics.
Chlamydiaceae
Chlamydiae are obligate intracellular bacteria that cause serious diseases in humans and animals of veterinary significance. Sexually transmitted infections caused by C. trachomatis affect approximately 92 million men and women worldwide, leading to a variety of pathologies including urethritis, cervicitis, salpingitis, pelvic inflammatory disease, ectopic pregnancy and infertility. The pathogen also causes blinding trachoma, which is the leading cause of preventable blindness, primarily in underdeveloped countries. Chlamydia pneumoniae is a significant cause of respiratory infections, and there is evidence that these infections predispose individuals to atherosclerosis and perhaps other chronic conditions. Veterinary infections by a set of different chlamydiae lead to epidemic in a diverse collection of species, and some of these can manifest as zoonoses in humans having contact with infected animals. Chlamydia psittaci, one such zoonotic agent, is considered a potential biothreat agent. Preparedness for both biodefense and for the public health challenges posed by C. burnetii requires the development of new antibacterial therapeutics.
Coxiellaceae
Coxiella burnetii is a zoonotic pathogen of ruminants that can be acquired by humans through contact with infected aerosols. C. burnetti is the etiologic agent of Q fever. Following an initial flu-like illness, which occurs within 2-3 weeks of exposure to the bacteria, a subset of Q fever patients develop pneumonia or hepatitis. 1%-2% of people with acute Q fever die of the disease. Acute infections can also give rise to chronic disease, which may lead to endocarditis and death in infected individuals. C. burnetii is a highly infectious agent that is rather resistant to heat and drying. It can become airborne and inhaled by humans. A single C. burnetii organism may cause disease in a susceptible person. This agent could be developed for use in biological warfare and is considered a potential terrorist threat. Current treatment options for acute disease include doxycycline. For chronic disease treatment, protocols combine doxycycline and quinolones. Preparedness for both biodefense and for the public health challenges posed by C. burnetii requires the development of new antibacterial therapeutics.